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      Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate

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          Abstract

          This study provides a new method for quantifying the cyclotide kalata B1 in both plasma and brain homogenate. Cyclotides are ultra‐stable peptides with three disulfide bonds that are interesting from a drug development perspective as they can be used as scaffolds. In this study we describe a new validated LC‐MS/MS method with high sensitivity and specificity for kalata B1. The limit of quantification was 2 ng/mL in plasma and 5 ng/gmL in brain homogenate. The method was linear in the range 2–10,000 ng/mL for plasma and 5–2000 ng/g for brain. Liquid Chromatographic separation was performed on a HyPurity C18 column, 50 × 4.6 mm, 3 µm particle size. The method had inter‐ and intra‐day precision and accuracy levels <15% and 12% respectively. Applying the method to in vivo plasma samples and brain homogenate samples from equilibrium dialysis yielded satisfying results and was able to describe the plasma pharmacokinetics and brain tissue binding of kalata B1. The described method is quick, reproducible and well suited to quantifying kalata B1 in biological matrices.

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          Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif.

          D J Craik, N Daly, T. Bond … (1999)
          Several macrocyclic peptides ( approximately 30 amino acids), with diverse biological activities, have been isolated from the Rubiaceae and Violaceae plant families over recent years. We have significantly expanded the range of known macrocyclic peptides with the discovery of 16 novel peptides from extracts of Viola hederaceae, Viola odorata and Oldenlandia affinis. The Viola plants had not previously been examined for these peptides and thus represent novel species in which these unusual macrocyclic peptides are produced. Further, we have determined the three-dimensional structure of one of these novel peptides, cycloviolacin O1, using (1)H NMR spectroscopy. The structure consists of a distorted triple-stranded beta-sheet and a cystine-knot arrangement of the disulfide bonds. This structure is similar to kalata B1 and circulin A, the only two macrocyclic peptides for which a structure was available, suggesting that despite the sequence variation throughout the peptides they form a family in which the overall fold is conserved. We refer to these peptides as the cyclotide family and their embedded topology as the cyclic cystine knot (CCK) motif. The unique cyclic and knotted nature of these molecules makes them a fascinating example of topologically complex proteins. Examination of the sequences reveals they can be separated into two subfamilies, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularization of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip. Here we define the structural features of the two apparent subfamilies of the CCK peptides which may be significant for the likely defense related role of these peptides within plants. Copyright 1999 Academic Press.
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            Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery.

            T Maurer, J Cory Kalvass (2002)
            Relative plasma, brain and cerebrospinal fluid (CSF) exposures and unbound fractions in plasma and brain were examined for 18 proprietary compounds in rats. The relationship between in vivo brain-to-plasma ratio and in vitro plasma-to-brain unbound fraction (fu) was examined. In addition, plasma fu and brain fu were examined for their relationship to in vivo CSF-to-plasma and CSF-to-brain ratios, respectively. Findings were delineated based on the presence or absence of active efflux. Finally, the same comparisons were examined in FVB vs. MDR 1a/1b knockout mice for a selected P-glycoprotein (Pgp) substrate. For the nine compounds without indications of active efflux, predictive correlations were observed between ratios of brain-to-plasma exposure and plasma-to-brain fu (r(2) = 0.98), CSF-to-brain exposure vs. brain fu (r(2) = 0.72), and CSF-to-plasma exposure vs. plasma fu (r(2) = 0.82). For the nine compounds with indications of active efflux, nonspecific binding data tended to over predict the brain-to-plasma and CSF-to-plasma exposure ratios. Interestingly, CSF-to-brain exposure ratio was consistently under predicted by brain fu for this set. Using a select Pgp substrate, it was demonstrated that the brain-to-plasma exposure ratio was identical to that predicted by plasma-to-brain fu ratio in MDR 1a/1b knockout mice. In FVB mice, plasma-to-brain fu over predicted brain-to-plasma exposure ratio to the same degree as the difference in brain-to-plasma exposure ratio between MDR 1a/1b and FVB mice. Consistent results were obtained in rats, suggesting a similar kinetic behavior between species. These data illustrate how an understanding of relative tissue binding (plasma, brain) can allow for a quantitative examination of active processes that determine CNS exposure. The general applicability of this approach offers advantages over species- and mechanism-specific approaches. Copyright 2002 John Wiley & Sons, Ltd.
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              Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis.

              C. Jennings, J. West, C Waine … (2001)
              Several members of the Rubiaceae and Violaceae families produce a series of cyclotides or macrocyclic peptides of 29-31 amino acids with an embedded cystine knot. We aim to understand the mechanism of synthesis of cyclic peptides in plants and have isolated a cDNA clone that encodes the cyclotide kalata B1 as well as three other clones for related cyclotides from the African plant Oldenlandia affinis. The cDNA clones encode prepropeptides with a 20-aa signal sequence, an N-terminal prosequence of 46-68 amino acids and one, two, or three cyclotide domains separated by regions of about 25 aa. The corresponding cyclotides have been isolated from plant material, indicating that the cyclotide domains are excised and cyclized from all four predicted precursor proteins. The exact processing site is likely to lie on the N-terminal side of the strongly conserved GlyLeuPro or SerLeuPro sequence that flanks both sides of the cyclotide domain. Cyclotides have previously been assigned an antimicrobial function; here we describe a potent inhibitory effect on the growth and development of larvae from the Lepidopteran species Helicoverpa punctigera.
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                Author and article information

                Contributors
                Erik Melander: erik.melander@farmbio.uu.se
                Journal
                Journal ID (nlm-ta): Biopolymers
                Journal ID (iso-abbrev): Biopolymers
                Journal ID (doi): 10.1002/(ISSN)1097-0282a
                Journal ID (publisher-id): BIP
                Title: Biopolymers
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0006-3525
                ISSN (Electronic): 1097-0282
                Publication date (Electronic): 23 November 2016
                Publication date (Print): November 2016
                Volume: 106
                Issue: 6 ( doiID: 10.1002/bip.v106.6 )
                Pages: 910-916
                Affiliations
                [ 1 ] Department of Pharmaceutical BiosciencesFaculty of Pharmacy, Uppsala University UppsalaSweden
                [ 2 ] Division of Pharmacognosy, Department of Medicinal ChemistryFaculty of Pharmacy, Uppsala University UppsalaSweden
                Author notes
                [*] [* ] Correspondence Erik Melander, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University. Email: erik.melander@ 123456farmbio.uu.se
                Article
                Publisher ID: BIP22984
                DOI: 10.1002/bip.22984
                PMC ID: 5132104
                PubMed ID: 27603276
                SO-VID: b393c607-e0cb-4513-a5fa-33771ea9ed2b
                Copyright © © 2016 The Authors Biopolymers Published by Wiley Periodicals, Inc.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 22 March 2016
                Date revision received : 28 August 2016
                Date accepted : 01 September 2016
                Page count
                Figures: 3, Tables: 1, Pages: 8, Words: 3637
                Funding
                Funded by: Uppsala University
                Award ID: #2012‐5063
                Award ID: #2011‐4339
                Categories
                Subject: Article
                Subject: Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id bip22984
                cover-date November 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:01.12.2016

                ScienceOpen disciplines: Biochemistry
                Keywords: brain,cyclotides,kalata b1,liquid chromatography,mass spectrometry,pharmacokinetics
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: brain, cyclotides, kalata b1, liquid chromatography, mass spectrometry, pharmacokinetics

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